U.S. patent number 7,064,208 [Application Number 11/300,864] was granted by the patent office on 2006-06-20 for substantially pure cilostazol and processes for making same.
This patent grant is currently assigned to Teva Pharmaceutical Industries, Ltd.. Invention is credited to Nina Finkelstein, Marioara Mendelovici, Gideon Pilarski.
United States Patent |
7,064,208 |
Mendelovici , et
al. |
June 20, 2006 |
**Please see images for:
( Certificate of Correction ) ** |
Substantially pure cilostazol and processes for making same
Abstract
The present invention provides substantially pure cilostazol.
The present invention also provides cilostazol particles that have
reduced particle size.
Inventors: |
Mendelovici; Marioara (Rehovot,
IL), Finkelstein; Nina (Herzliya, IL),
Pilarski; Gideon (Holon, IL) |
Assignee: |
Teva Pharmaceutical Industries,
Ltd. (Petah Tiqva, IL)
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Family
ID: |
46281814 |
Appl.
No.: |
11/300,864 |
Filed: |
December 14, 2005 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20060094757 A1 |
May 4, 2006 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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10951570 |
Sep 27, 2004 |
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10336721 |
Jan 6, 2003 |
6825214 |
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09929683 |
Aug 14, 2001 |
6515128 |
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60190588 |
Mar 20, 2000 |
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60225362 |
Aug 14, 2000 |
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Current U.S.
Class: |
546/158 |
Current CPC
Class: |
C07C
231/02 (20130101); C07D 215/227 (20130101); C07D
401/12 (20130101); C07D 403/12 (20130101); C07C
231/02 (20130101); C07C 233/25 (20130101) |
Current International
Class: |
C07D
215/36 (20060101) |
Field of
Search: |
;546/158 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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09124605 |
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May 1997 |
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JP |
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10330262 |
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Dec 1998 |
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JP |
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2000-229944 |
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Aug 2000 |
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JP |
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Primary Examiner: Morris; Patricia L.
Attorney, Agent or Firm: Kenyon &Kenyon LLP
Parent Case Text
RELATED APPLICATIONS
This application is a divisional application of U.S. application
Ser. No. 10/951,570, filed on Sep. 27, 2004, which is a
continuation of application Ser. No. 10/336,721, filed on Jan. 6,
2003, now U.S. Pat. No. 6,825,214, which is a continuation-in-part
of application Ser. No. 09/929,683 filed on Aug. 14, 2001, now U.S.
Pat. No. 6,515,128 which claims benefit of U.S. provisional
application Nos. 60/190,588, filed on Mar. 20, 2000 and 60/225,362,
filed on Aug. 14, 2000.
Claims
We claim:
1. A process for preparing cilostazol comprising: a) combining
6-hydroxy-3,4-dihydroquinolinone and at least one alkali metal
hydroxide; b) removing water using molecular sieves; c) adding
1-cyclohexyl-5-(4-halobutyl)-tetrazole; and d) recovering
cilostazol.
2. The process according to claim 1, wherein the alkali metal
hydroxide is sodium hydroxide or potassium hydroxide.
3. The process according to claim 1, wherein the alkali metal
hydroxide is sodium hydroxide.
4. The process according to claim 1, wherein the alkali metal
hydroxide is present in an amount of about 0.9 to about 1.2
equivalents with respect to 6-hydroxy-3,4-dihydroquinolinone.
5. The process according to claim 1, wherein the molecular sieves
have a size of three or four angstroms.
6. The process according to claim 1, wherein the molecular sieves
have a size of three angstroms.
7. The process according to claim 1, further comprising a solvent
selected from the group consisting of 1-butanol, isopropanol,
2-butanol, and amyl alcohol.
8. The process according to claim 7, wherein removing water is
performed by placing the molecular sieves in a soxlet extraction
funnel or a reservoir of a dropping funnel and heating to reflux to
allow water vapor to circulate through the sieves.
9. The process according to claim 1, wherein the
1-cyclohexyl-5-(4-halobutyl)-tetrazole is present in about 0.9 to
about 0.99 equivalents with respect to
6-hydroxy-3,4-dihydroquinolinone.
Description
FIELD OF THE INVENTION
The present invention relates to processes for preparing
cilostazol.
BACKGROUND OF THE INVENTION
The present invention pertains to processes for preparing
6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone
of formula (I)
##STR00001## which is also known by the generic name cilostazol.
Cilostazol inhibits cell platelet aggregation and is used to treat
patients with intermittent claudication.
Cilostazol is described in U.S. Pat. No. 4,277,479 ("the '479
patent"), which teaches a preparation wherein the phenol group of
6-hydroxy-3,4-dihydroquinolinone ("6-HQ") of formula (II) is
alkylated with a 1-cyclohexyl-5-(4-halobutyl)-tetrazole ("the
tetrazole") of formula (III). It is recommended to use an equimolar
or excess amount up to two molar equivalents of the tetrazole
(III).
##STR00002##
The '479 patent mentions a wide variety of bases that may be used
to promote the alkylation reaction, namely, sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium bicarbonate, silver carbonate, elemental
sodium, elemental potassium, sodium methylate, sodium ethylate,
triethylamine, pyridine, N,N-dimethylaniline, N-methylmorpholine,
4-dimethylaminopyridine, 1,5-diaza-bicyclo[4,3,0]-non-5-ene,
1,5-diaza-bicyclo[5,4,0]-undec-7-ene ("DBU"), and
1,4-diaza-bicyclo[2,2,2]octane.
The '479 patent states that the alkylation may be conducted neat or
in solvent. Suitable solvents are said to be methanol, ethanol,
propanol, butanol, ethylene glycol, dimethyl ether,
tetrahydrofuran, dioxane, monoglyme, diglyme, acetone,
methylethylketone, benzene, toluene, xylene, methyl acetate, ethyl
acetate, N,N-dimethylformamide, dimethylsulfoxide and
hexamethylphosphoryl triamide.
According to Examples 4 and 26 of the '479 patent, cilostazol was
prepared using DBU as base and ethanol as solvent.
In Nishi, T. et al. Chem. Pharm. Bull. 1983, 31, 1151 57, a
preparation of cilostazol is described wherein 6-HQ is reacted with
1.2 molar equivalents of
5-(4-chlorobutyl)-1-cyclohexyl-1H-tetraazole ("CHCBT," tetrazole
III wherein X.dbd.Cl) in isopropanol with potassium hydroxide as
base. Cilostazol was obtained in 74% yield.
One reason for using an excess of tetrazole as was done in Nishi et
al. and recommended by the '479 patent is that CHCBT is unstable to
some bases. When exposed to an alkali metal hydroxide in water for
a sufficient period, CHCBT undergoes elimination and cyclization to
yield byproducts (IV) and (V).
##STR00003##
Nishi et al.'s reported yield is based upon the limiting reagent
6-HQ. The yield with respect to CHCBT is 69%. In the economics of
producing a chemical on a large scale, improvements in chemical
yield are rewarded with savings in the chemical's production cost.
CHCBT is an expensive compound to prepare and should not be wasted.
It would be highly desirable to be able to realize further
improvement in yield of the alkylation of 6-HQ with CHCBT and its
halogen analogs in a way that lowers the cost of producing
cilostazol. In other words, it would be desirable to further
improve the yield of cilostazol by increasing the degree of
conversion of CHCBT to cilostazol, as opposed to, for example,
improving the yield calculated from 6-HQ by increasing the excess
of tetrazole or manipulating the reaction conditions in a way that
increases the conversion of 6-HQ to cilostazol but at the expense
of poorer conversion of CHCBT to cilostazol.
Although CHCBT is unstable to hydroxide ion, it is relatively
stable in the presence of non-nucleophilic organic bases. There are
advantages to using inorganic bases, however, that favor their
selection over organic bases. Firstly, the phenolic proton of 6-HQ
is labile. Thus, relatively non-caustic and easily handled
inorganic bases may be used to prepare cilostazol. Further,
inorganic bases are easier to separate from the product and are
less toxic to the environment when disposed than organic bases are.
Therefore, it would also be highly desirable to use an inorganic
base while realizing an improvement in conversion of CHCBT to
cilostazol.
SUMMARY OF THE INVENTION
The present invention provides improved processes for preparing
cilostazol (I) by alkylating the phenol group of 6-HQ with the
.delta. carbon of a 5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole.
In a first aspect, the invention provides a process wherein 6-HQ
and a water soluble base are dissolved in water. A
1-cyclohexyl-5-(4-halobutyl)-tetrazole is dissolved in a
water-immiscible organic solvent. The two solutions are combined in
the presence of a quaternary ammonium salt phase transfer catalyst
to form a biphasic mixture in which the 6-HQ and tetrazole react to
produce cilostazol. The purity of the cilostazol may be detected by
reversed-phase high performance liquid chromatography (HPLC) using
gradient elution. The process may be practiced by a variety of
procedures taught by the present invention. In one variation, a
reaction promoter, like sodium sulfate, is added to accelerate
phase transfer of 6-HQ into the organic solvent.
Another aspect of the present invention provides a preparation of
cilostazol from a single phase reaction mixture of 6-HQ and a
1-cyclohexyl-5-(4-halobutyl)tetrazole and a mixture of inorganic
bases. The base mixture comprises an alkali metal hydroxide and
alkali metal carbonate. This process minimizes decomposition of the
starting tetrazole and cilostazol by buffering the pH which results
in improved yield calculated based upon the tetrazole, the more
precious of the two organic starting materials. A preferred
embodiment wherein the alkali metal hydroxide is added portionwise
minimizes the formation of dimeric byproducts. In another preferred
embodiment of the homogeneous process, the reaction mixture is
dehydrated with molecular sieves before the tetrazole is added.
Yet another aspect of the present invention provides a
pharmaceutical composition comprising substantially pure cilostazol
obtained by the methods of the present invention described above.
By "substantially pure" is meant having a purity equal to or
greater than 98%.
Another aspect of the present invention provides a pharmaceutical
composition comprising cilostazol particles of reduced particle
size. By "reduced particle size" is meant about 90% of the
particles having a diameter equal to or less than about 60 microns
(d(0.9).ltoreq.60 microns). The reduced particle size may be
obtained by fine-milling or micronization.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparing cilostazol
(I) by alkylating the phenol group of 6-HQ with the .delta. carbon
of a 5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole ("the tetrazole").
The transformation itself, depicted in Scheme 1 is known.
##STR00004##
The present invention improves upon processes previously used to
perform the chemical transformation depicted in Scheme 1 which
result in a greater conversion of the tetrazole starting material
to cilostazol. The improvements may be viewed as falling into one
of two aspects of the present invention: (1) a heterogeneous, or
biphasic, process employing phase transfer catalysis and
improvements applicable to the heterogeneous process and (2)
improvements applicable to a homogeneous process.
In a first aspect, the present invention provides a biphasic
process for preparing cilostazol by alkylating the phenol group of
6-HQ with a 5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole using
controlled phase transfer methodology. For a discussion of the
theory and general application of phase transfer catalysis, See,
Dehmlow, E. V.; Dehmlow, S. S., Phase Transfer Catalysis 3rd ed.
(VCH Publishers: New York 1993).
According to the present inventive process, a solution of 6-HQ, a
water-soluble base and a trialkyl ammonium phase transfer catalyst
in water is contacted with a solution of a
5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole in a water-immiscible
organic solvent for a period of time sufficient to cause the
tetrazole to be substantially completely converted to cilostazol
and then separating the cilostazol from the biphasic mixture.
The biphasic reaction mixture separates the base from the base
sensitive tetrazole. Although not intending to be bound by any
particular theory, it is believed that the 6-HQ phenolate anion
complexes with the tetra-alkyl ammonium ion which increases its
solubility in the water-immiscible organic solvent. The complexed
phenolate then enters the water-immiscible phase and reacts with
the tetrazole there.
Suitable phase transfer catalysts are ammonium salts such as
tricaprylylmethylammonium chloride (Aliquat.RTM. 336),
tetra-n-butylammonium bromide ("TBAB"), benzyltriethylammonium
chloride ("TEBA"), cetyltrimethylammonium bromide, cetylpyridinium
bromide, N-benzylquininium chloride, tetra-n-butylammonium
chloride, tetra-n-butylammonium hydroxide, tetra-n-butylammonium
iodide, tetra-ethylammonium chloride, benzyltributylammonium
bromide, benzyltriethylammonium bromide, hexadecyltriethylammonium
chloride, tetramethylamrnmonium chloride, hexadecyltrimethyl
ammonium chloride, and octyltrimethylammonium chloride. More
preferred phase transfer catalysts are Aliquat.RTM. 336, TBAB, TEBA
and mixtures thereof, the most preferred being Aliquat.RTM. 336.
The phase transfer catalyst may be used in a stoichiometric or
substoichiometric amount, preferably from about 0.05 to about 0.25
equivalents with respect to the tetrazole.
Suitable bases are soluble in water but poorly soluble or insoluble
in water-immiscible organic solvents. Such bases are typically
metal salts of inorganic counterions. Preferred inorganic bases are
hydroxide and carbonate salts of alkali metals. More preferred
inorganic bases are NaOH, KOH, K.sub.2CO.sub.3, Na.sub.2CO.sub.3
and NaHCO.sub.3. The most preferred inorganic base in the
heterogeneous process is NaOH.
The halogen atom of 5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole (X in
formula III) may be chlorine, bromine or iodine, preferably
chlorine. Although the tetrazole may be used in any amount desired,
it is most desirable to use a stoichiometric amount of tetrazole or
less relative to 6-HQ, more preferably about 0.9 molar
equivalents.
Preferred water-immiscible solvents are toluene, hexanes,
dichloromethane and mixtures thereof. An excess of water to
water-immiscible solvent is preferred, although the ratio may vary
widely. Preferred ratios of water to water-immiscible solvent range
from about 0.5:1 to about 8:1 (v/v), more preferably from about 1:1
to about 6:1.
According to one preferred procedure for preparing cilostazol, the
6-HQ, water-soluble base and phase transfer catalyst are dissolved
in water. The tetrazole is dissolved in the water-immiscible
solvent and the two solutions are contacted and agitated, with
optional heating, until the tetrazole is substantially consumed.
Cilostazol may be isolated by cooling the reaction mixture to
precipitate the cilostazol and then filtering or decanting the
solutions. Cilostazol may be purified by methods shown in Table 1
or any conventional method known in the art, including, for
example, RP-HPLC using gradient elution, as discussed above.
Alternatively, a biphasic mixture of the water-miscible organic
solvent and the aqueous solution of 6-HQ, water-soluble base and
the phase transfer catalyst is mixed and optionally heated while
the tetrazole is slowly added to the stirred mixture. The slow
addition of the tetrazole may be either continuous or
portionwise.
In yet another alternative procedure, an aqueous suspension of 6-HQ
and the phase transfer catalyst are contacted with the solution of
tetrazole in the water-immiscible organic solvent. The biphasic
mixture is agitated and optionally heated, while the water-soluble
base is slowly added to the mixture. The slow addition may be
either continuous as in a concentrated aqueous solution of the base
or portionwise.
Each of these preferred procedures may be modified to take
advantage of a further improvement, which is to add a reaction
promoter to the aqueous phase. Reaction promoters are salts like
sodium sulfate and potassium sulfate that increase the ionic
strength of aqueous solutions but do not form strongly acidic or
basic aqueous solutions. The reaction promoters decrease the
solubility of 6-HQ in the aqueous phase and improve the efficiency
of phase transfer to the organic phase. The preferred reaction
promoter is sodium sulfate. Preferably, the reaction promoter is
added in the amount of about 12 16% (w/v) with respect to the
aqueous phase.
In a second aspect, the present invention provides a process for
preparing cilostazol by alkylating the phenol group of 6-HQ with a
5-(4-halobutyl)-1-cyclohexyl-1H-tetrazole in a single liquid phase
reaction mixture. 6-HQ and the tetrazole may be used in any amount,
though it is preferred that the tetrazole be the limiting reagent,
preferably used in from about 0.9 to about 0.99 equivalents with
respect to the 6-HQ. Suitable solvents for forming the single
liquid phase reaction mixture of this aspect of the invention are
non-aqueous hydroxylic solvents, which include 1-butanol,
isopropanol, 2-butanol and amyl alcohol.
In this process, two inorganic bases are used to catalyze the
reaction. One of the bases is an alkali metal hydroxide such as
sodium or potassium hydroxide. The other base is an alkali metal
carbonate such as sodium or potassium carbonate. The most preferred
alkali metal is potassium. Thus, preferred base mixtures are
mixtures of potassium hydroxide and potassium carbonate. The alkali
metal hydroxide is preferably used in an amount of from about 0.9
to about 1.2 equivalents with respect to the 6-HQ and the alkali
metal carbonate is preferably used in an amount of about 0.1 to
about 0.2 equivalents with respect to the 6-HQ.
The 6-HQ, tetrazole, alkali metal hydroxide and alkali metal
carbonate may be added to the non-aqueous solvent in any order
desired and at any rate desired.
In one preferred procedure, 6-HQ, the tetrazole and the alkali
metal carbonate are added to the hydroxylic solvent along with a
portion, e.g. about a one-fourth portion, of the alkali metal
hydroxide. Thereafter, the remainder of the alkali metal hydroxide
is added portionwise to the reaction mixture. It has been found
that portionwise addition of the alkali metal hydroxide suppresses
a byproduct that forms by the substitution of the halogen of the
tetrazole by the 6-HQ lactam nitrogen.
Molecular sieves may be used to remove water from the single liquid
phase reaction mixture before the tetrazole is added. Three and
four angstrom molecular sieves are preferred, with three angstrom
sieves being most preferred. The molecular sieves may be stirred
with the solution to remove water formed by deprotonation of 6-HQ
by KOH or adventitious water. Preferably, the molecular sieves are
placed in a soxlet extraction funnel, the reservoir of a dropping
funnel, or other suitable apparatus mounted on the reaction vessel
that will allow circulation of vapor through the molecular sieves
and return of the condensate to the reaction vessel. The solution
is then refluxed to circulate water vapor over the molecular
sieves. After the solution of 6-HQ phenolate has been dehydrated,
the tetrazole is added to the solution to react with the 6-HQ
phenolate to produce cilostazol.
In the process of Nishi et al., it was necessary to separate
unreacted starting materials and the organic base by column
chromatography. It is desirable in a large scale process to avoid
chromatography and concomitant production of spent solid phase. We
have further discovered that cilostazol prepared according to the
teachings of the present invention or by other methods can be
selectively crystallized from certain solvents in high purity
without the need for "clean up" chromatography to remove, for
example, unreacted starting materials. Suitable recrystallization
solvents are 1-butanol, acetone, toluene, methyl ethyl ketone,
dichloromethane, ethyl acetate, methyl t-butyl ether, dimethyl
acetamide-water mixtures, THF, methanol, isopropanol, benzyl
alcohol, 2-pyrrolidone, acetonitrile, Cellosolve, monoglyme,
isobutyl acetate, sec-butanol, tert-butanol, DMF, chloroform,
diethyl ether and mixtures thereof.
The purity of the cilostazol may be detected by any means known in
the art, including, for example, high performance liquid
chromatography (HPLC), such as reversed-phase HPLC (RP-HPLC) using
gradient elution. As is known in the art, gradient elution involves
steady changes in the mobile phase composition during the
chromatographic run. For determining the purity of cilostazol
crystalized according to the present invention, a RP-8 column
should be used. The eluent components of the mobile phase are water
and acetonitrile and the mobile phase is preferably controlled by a
gradient program starting with an initial element of 100% water
until a 1:1 ratio of the two components is obtained. The
chromatographic system is equipped with an ultraviolet detector set
at 254 nanometers. This RP-HPLC method allows the detection of
cilostazol-related impurities until a level of at least 0.02%
relative to the sample concentration.
In a further aspect of the present invention, when a pharmaceutical
composition comprising cilostazol prepared according to the present
invention is formulated for oral administration, the compound is
preferably processed to have a reduced small particle size. Methods
of obtaining reduced particle size of a compound are well known in
the art and include, for example, processes such as fine-milling
and micronization. Accordingly, in one embodiment of the present
invention, the cilostazol prepared according to the present
invention is fine-milled under suitable conditions of mill rotation
rate and feed rate to where 90% of the particles have a diameter of
about 60 microns. In another embodiment, the cilostazol is
micronized by being passed through an air jet mill at a suitable
feed air pressure, grinding air pressure, feed rate, and rotation
rate to where 90% of the particles have a diameter equal to or less
than about 15 microns. The cilostazol may then be formulated into a
pharmaceutical composition or dosage form further comprising one or
more pharmaceutically acceptable excipients. Such compositions and
dosage forms include, for example, compacted tablets, powder
suspensions, capsules, and the like.
The invention will now be further illustrated with the following
examples, which offer highly specific procedures that may be
followed in practicing the invention but which should not be
construed as limiting the invention in any way.
EXAMPLES
Example 1
Preparation of Cilostazol Using A Phase Transfer Catalyst
A 1 L reactor was charged with 6-HQ (16.5 g, 0.1011 moles), and
NaOH (1 eq.) in water (90 ml). To this solution was add toluene (15
ml) and CHCBT (22.22 g, 0.0915 moles), Na.sub.2SO.sub.4 (17 g) and
catalyst (1.9 g) (aliquat 336). The mixture was heated to reflux
for 8 h. After this period of time, the mixture was cooled to room
temperature, the solid was filtered and washed with water and
methanol to afford the crude product (29 g, yield 88%; purity by
reversed-phase HPLC using gradient elution .about.99%).
Example 2
Preparation of Cilostazol with Addition of CHCBT in One Portion
6-HQ (10 g, 0.0613 moles), KOH (4.05 g, 0.0722 moles),
K.sub.2CO.sub.3 (1.5 g, 0.011 mole), CHCBT (18 g, 0.0742 moles) and
n-BuOH (130 ml) were heated at reflux for .about.5 hours. After
cooling of the reaction mixture to room temperature the solid was
filtered, washed with n-BuOH and water. The crude product (19.7 g,
85% yield, 98.7% pure) was recrystallized from n-BuOH (10 vol.) to
give cilostazol crystals (yield 94%, 99.6% pure).
Example 3
Preparation of Cilostazol by Addition of The Base in Portions
6-HQ (10 g, 0.0613 moles), KOH (1.01 g, 0.018 mole),
K.sub.2CO.sub.3 (1.5 g, 0.011 mole), CHCBT (13.4 g, 0.0552 moles)
and 130 ml n-BuOH were heated at reflux for 1 hour. After 1 hour, a
second 1.1 g portion of KOH was added and the reflux was continued.
The procedure was repeated with two additional 1.1 g portions of
KOH. After the addition of the whole KOH the reaction was continued
for an additional hour. The reaction mixture was cooled to room
temperature, the solid was filtered and washed with n-BuOH and
dried to afford the product (15.6 g, 56% yield, 98.3% pure).
Example 4
Preparation of Cilostazol Using Molecular Sieves as Dehydrating
Agent
A three neck flask equipped with condenser and a soxlet extraction
funnel containing molecular sieves 3 .ANG. (28 g) was charged with
6-HQ (10 g, 0.0613 moles), KOH (4.05 g, 0.0722 moles) and
K.sub.2CO.sub.3 (1.5 g, 0.011 moles) and 130 ml n-BuOH. The mixture
was heated to reflux and the reflux was maintained passing the
solvent over the molecular sieves. After 30 minutes, CHCBT (18 g,
0.0742 moles, 1.2 equivalents) was added and the reflux was
continued for about 5h. Then, the reaction mixture was cooled and
the product was filtered and washed with n-BuOH. The yield after
drying was 14.4 g (62%, 98.3% pure).
Example 5
Preparation of Cilostazol Using an Excess of 6-HQ
6-HQ (10 g, 0.0613 moles), KOH (4.05 g, 0.0722 moles),
K.sub.2CO.sub.3 (1.5 g, 0.011 mole), CHCBT (13.4 g, 0.0552 moles)
and 130 ml n-BuOH were heated at reflux for 5 hours. After cooling
of the reaction mixture to room temperature the solid was filtered
and washed with n-BuOH and water; the material was dried to give
the product cilostazol (15.93 g, 76.2% yield, 98.5% pure).
Example 6
Crystallization of Cilostazol From Recrystallization Solvents
Table 1 provides conditions for selectively crystallizing
cilostazol from mixtures containing minor amounts of 6-HQ and CHCBT
and obtaining substantially pure cilostazol.
TABLE-US-00001 TABLE 1 Example Solvent Volume* Recommended
Procedure Purity 6 n-BuOH 10 97.2 7 n-BuOH 20 98.1 8 Acetone 20
Slurry. Reflux. Cool to r.t. 98.65 9 Toluene 20 Dissolve at reflux.
Cool to r.t. 98.60 10 Methyl ethyl ketone 11 Dissolve at reflux.
Cool to r.t. 99.33 11 CH.sub.2Cl.sub.2 4 Dissolve at reflux. Cool
to r.t. 98.82 12 Ethyl acetate 10 Slurry at reflux 1 h. Cool to
r.t. 97.50 13 MTBE 10 Slurry at reflux 1 h. Cool to r.t. 94.06 14
2:1 DMA-H2O 10 Dissolve in DMA at ~70 80.degree. C. Add water. Cool
to r.t. Precipitate at 65.degree. C. 15 THE 13 Dissolve at reflux.
Cool to r.t. 16 Methanol 3 Dissolve at reflux. Cool to r.t. 99.16
Precipitate at 55.degree. C. 17 Acetone 2.5 Slurry at reflux for 1
h. Cool to 99.12 r.t. 18 Ethanol 12.5 Dissolve at reflux. Cool to
r.t. 98.90 19 Isopropanol 19 Dissolve at reflux. Cool to r.t. 98.75
20 Acetone 33 Dissolve at reflux. Cool to 40.degree. C. 98.90 21
Benzyl alcohol 2 Dissolve at 55.degree. C. Cool to r.t. 98.85 22
2-Pyrrolidone 3.5 Dissolve at 65.degree. C. Cool to r.t. 23
Acetonitrile 6.5 Dissolve at reflux. Cool to 30.degree. C. 98.70 24
2-BuOH 5 Dissolve at ~90.degree. C. Cool to r.t. 94.80 25
Cellosolve 3 Dissolve at ~100.degree. C. Cool to r.t. 98.80 26
Monoglyme 13 Dissolve at reflux. Cool to r.t. 97.06 27
iso-butyl-acetate 23 Dissolve at reflux (115.degree. C.). Cool
97.50 to r.t. 28 n-BuOH 20 Dissolve at reflux. Treat with 99.14
decolorizing agents, (SX1 activated carbon and tonsil silicate).
Cool to r.t. 29 MeOH 10 Dissolve at reflux. Cool to r.t. 99.92 30
MeOH 10 Dissolve at reflux. Cool to r.t. 99.93 31 MeOH 10 Dissolve
at reflux. Cool to r.t. 99.95 *Relative to the volume of
cilostazol
Example 32
Reduction of Particle Size and Particle Size Distribution of
Cilostazol
Cilostazol obtained from Examples 1 6, is fine-milled by being
passed through a pin mill at a mill rotation rate of 10500 rpm and
a feed rate of 15 kg/hr to where 90% of the cilostazol particles
have a diameter of about 60 microns.
Example 33
Cilostazol is micronized by being passed through an air jet mill at
a feed rate of 20 kg/hr, a feed air pressure of 7 bars, a grinding
air pressure of 4 bars to where 90% of the cilostazol particles
have a diameter of less than about 15 microns. The rotation rate of
the jet mill is 300 mm.
It should be understood that some modification, alteration and
substitution is anticipated and expected from those skilled in the
art without departing from the teachings of the invention.
Accordingly, it is appropriate that the following claims be
construed broadly and in a manner consistent with the scope and
spirit of the invention.
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